KDM5 inhibition offers a novel therapeutic strategy for the treatment of KMT2D mutant lymphomas

被引：37

作者：

Heward, James ^{[1
]}

Konali, Lola ^{[1
]}

D'Avola, Annalisa ^{[2
]}

Close, Karina ^{[1
]}

Yeomans, Alison ^{[2
]}

Philpott, Martin ^{[3
]}

Dunford, James ^{[3
]}

Rahim, Tahrima ^{[1
]}

Al Seraihi, Ahad F. ^{[1
]}

Wang, Jun ^{[1
]}

Korfi, Koorosh ^{[1
]}

Araf, Shamzah ^{[1
]}

Iqbal, Sameena ^{[1
]}

Bewicke-Copley, Findlay ^{[1
]}

Kumar, Emil ^{[1
]}

Barisic, Darko ^{[4
]}

Calaminici, Maria ^{[1
]}

Clear, Andrew ^{[1
]}

Gribben, John ^{[1
]}

Johnson, Peter ^{[2
]}

Neve, Richard ^{[5
]}

Cutillas, Pedro ^{[1
]}

Okosun, Jessica ^{[1
]}

Oppermann, Udo ^{[3
]}

Melnick, Ari ^{[4
]}

Packham, Graham ^{[2
]}

Fitzgibbon, Jude ^{[1
]}

机构：

[1] Queen Mary Univ London, Barts Canc Inst, Haematooncol, London, England

[2] Univ Southampton, Southampton Gen Hosp, Canc Res UK Ctr, Canc Sci,Fac Med, Southampton, Hants, England

[3] Univ Oxford, Nuffield Dept Orthopaed Rheumatol & Musculoskelet, Oxford, England

[4] Weill Cornell Med, Dept Med, New York, NY USA

[5] Gilead Sci, Foster City, CA USA

来源：

BLOOD | 2021年 / 138卷 / 05期

基金：

英国医学研究理事会; 美国国家卫生研究院;

关键词：

SELECTIVE-INHIBITION; EZH2; MUTATIONS; CELL; GENE; EXPRESSION; GENOME; CANCER; FAMILY; INACTIVATION; DEMETHYLASES;

D O I：

10.1182/blood.2020008743

中图分类号：

R5 [内科学];

学科分类号：

1002 ; 100201 ;

摘要：

Loss-of-function mutations in KMT2D are a striking feature of germinal center (GC) lymphomas, resulting in decreased histone 3 lysine 4 (H3K4) methylation and altered gene expression. We hypothesized that inhibition of the KDM5 family, which demethylates H3K4me3/me2, would reestablish H3K4 methylation and restore the expression of genes repressed on loss of KMT2D. KDM5 inhibition increased H3K4me3 levels and caused an antiproliferative response in vitro, which was markedly greater in both endogenous and gene-edited KMT2D mutant diffuse large B-cell lymphoma cell lines, whereas tumor growth was inhibited in KMT2D mutant xenografts in vivo. KDM5 inhibition reactivated both KMT2D-dependent and -independent genes, resulting in diminished B-cell signaling and altered expression of B-cell lymphoma 2 (BCL2) family members, including BCL2 itself. KDM5 inhibition may offer an effective therapeutic strategy for ameliorating KMT2D loss-of-function mutations in GC lymphomas.

引用

页码：370 / 381

页数：12

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